In 1990 the German Federal Institute of Drugs and Medicinnal Products (BfArM) published a monograph on Meliloti Herba, in which the use of melilot is indicated for symptoms and signs in chronic venous insufficiency like pains; adjuvant treatment of thrombophlebitis and lymphostasis. Scheel et al. (Microbiol Toxins 8: 47-66, 1972) reported that coumarins have anti-bacterial, anti-viral and anti-tumor effects. Kovach et al (Arzeim-Forsch/Drug Res 20: 1630-33, 1970) proved that coumarins can increase blood flow and improve myocardial ischemia. Casley-Smith, (Vasomed 6: 232-4, 1994), Gaffney (J Pathol 133: 229-42, 1981), Piller (Br J Exp Pathol 59: 319-26, 1978), and Knight (Clin Sci 77: 69-76, 1989) showed that coumarins have effects of endothelial system protection and lymph-circulation promotion, etc. Nair et al. (Carcinogenesis 12 (1): 65-69, 1991) reported the anticancer activity of coumarins compounds. Ishizuka et al. (U.S. Pat. No. 5,096,924) proved that substituted coumarins have anticancer activities. Marshall et al. (J. Biol. Resp. Mod. 8: 62, 1989) reported that coumarins have immuno-enhancing effects, such as improving the antitumor abilities by remarkably raising monocytes of patients suffering from cancer. Preuss-Ueberschar et al. (Drug Res. 34: 1305-1313, 1984) showed that the coumarins are non-teratogenitic. Takagaki, Hidetsugu et al. (EP 0, 796, 854 A1, 1997) disclosed that 3-, 4-, or 7-hydroxy or alkoxy substituted coumarins' effects in treating heart diseases. Markal et al. (WO 98/25, 608, 1998) disclosed that substituted 4-arylcoumarins can be used to treat viral infections, such as herpes zoster or herpes simplex. Trkovnik et al. (WO 99/21550, 1999) reported that 4-methyl-7-hydroxycoumarin can be used to treat or prevent nephrocirrhosis, pancreatitis, and disorders in bladder or alimentary tracts. Takagaki et al. (Jpn. Kokai Tokkyo Koho JP 07277972, 1995) reported that coumarin derivatives can inhibit rat diabetes induced by streptozotocin. Scott et al. (U.S. Pat. No. 5,723,476, 1998) disclosed that 3-carboxamide-4-hydroxy coumarin compounds are effective to the non-insulin dependent diabetes models. Han, Xingmei et al. (Zhongguo Yaolixue Tongbao, 15(4): 332-5, 1999) reported that 6,7-dimethoxycoumarin is effective to acute renal failure induced by endotoxins. Allen et al. (PCT Int Appl WO 2001 019396 A1 2001) reported that the TGF-β1 antagonists may be used for the treatment or prophylaxis of chronic nephritis.
In our research, a series of coumarin derivatives were synthesized and their biological activities were evaluated. For example, Xiao-long Huang et al reported substituted 3-acetyl- and 3-glyoxal-coumarin derivatives possessing good anti-mutagenic effects (Yaoxue Xuebao 31(6): 431-436, 1996; ibid 31(7): 509-516, 1996). Shi-ping Xu et al discovered that the coumarin retinoids show potent differentiation inducing, anti-mutagenic, and anti-carcinogenic effects (Chinese patent application No. 97116602.1, CN1207392A). Song Xu et al.'s study on 6- or 7-substitutedstyryl-coumarins, 4-styryl-coumarins and 4-, 6- or 7-substitutedphenyliminomethylene-coumarins show anticancer effects (Yaoxue Xuebao 35(2): 103-107, 2000; ibid 36(4): 269-273, 2001; ibid 37(2): 113-116, 2002).
Following that, upon our continued research works on coumarins compounds, a series of novel coumarins and coumarin carboxamides were synthesized. And we have found that these coumarins carboxamide compounds possess potent inhibition effects on transforming growth factor β1 (TGF-β1), which has not been reported before. The TGF-β1 inhibitors may be used for the treatment of chronic renal dysfunctions and diabetic renal dysfunctions. Meanwhile, it can also significantly decrease angiotensin II (AngII). Therefore, the compounds of present invention, may be used in the drugs for the treatment of chronic renal failure, nephritis, hypertension, even cirrhosis of liver and pulmonary fibrosis. For example, Allen et al. (PCT Int Appl WO 2001 019396 A1 2001) reported that the TGF-β antagonists may be used for the treatment or prophylaxis of chronic nephritis.
Renal insufficiencies, particularly chronic renal failure, are the results of kidney injuries with various pathogenesis and progressive deterioration. Among the primary nephropathies, the most common is the chronic glomerulonephritis, and tubolointerstitial nephritic comes the second. Among the secondary nephropathies, diabetic nephropathy holds the first position. At present, diabetic nephropathy holds about 27% of the origin of chronic renal failures, and is still increasing; hypertensive nephropathy comes the second, about 22.7% and the glomerulonephritis comes next about 21.2% and all other pathogenesis occupy 26.6% in the origin of chronic renal insufficiencies. Being a common disease per se, nephropathies, no wonder what pathogenesis, or being immune or non-immune mechanism, unless promptly treated, may be result in chronic renal insufficiency and irreversible chronic renal injuries.
Upon the researches of the field, it shows that transforming growth factor-β1 (TGF-β1) has a close relationship with chronic renal insufficiencies caused by various pathogenesis. Four hours after nephrectomy, TGF-β1 began to increase and the renin-angiotensin system was consequently influenced. Continuously rising of TGF-β1 and over-expression will result in inhibiting the degradation of the extracellular matrix, promoting the matrix integration, and also relates to the proteinuria from renal insufficiency, as well as matrix fibrosis. Therefore, glomerular sclerosis and interstitial fibrosis have direct relationship with TGF-β1, and renin-angiotensin system and TGF-β1 are the two critical factors related to chronic renal insufficiencies. Moreover, as the inhibition of the former has close relationship with the decrease of TGF-β1 producing, this suggests that the increase of TGF-β1 might be an important pathogenesis of kidney injuries to the end-stage renal insufficiencies, and would be a new target for the screening of new anti-renal failure drugs.
Coumarin compounds possess extensive biological activities, however, it haven't been reported in the literatures that these compounds can be used for the treatment of chronic renal failures. The present compounds are a novel type compounds and can remarkably inhibit TGF-β1, which is an important pathogenesis of kidney injuries to the end-stage renal failure. It has been proved that, the compound of present invention show satisfied effects on treating renal insufficiencies.
Renal insufficiencies, especially chronic renal insufficiencies, are chronic diseases that are hard to be cured. With the continuously increase of diabetes and hypertension, the incidence of renal insufficiencies becomes more and more, and has no effective drugs or other methods for the treatment or prophylaxis up to now. Therefore, the object of the present invention is to develop new drug for the treatment of renal insufficiencies.